CN1198735A - Benzenesulfonamide derivatives and their preparation and application in the medical field - Google Patents

Abstract

Benzenesulphonamide compounds of general formula (I), wherein R1 is a hydrogen or halogen atom such as chlorine or fluorine, or a straight or branched C1-4 alkyl or C1-4 alkoxy group, each of R2, R3 and R4, which are the same or different, is a hydrogen atom or a straight, branched or cyclic C1-4 alkyl group, and R5 is a hydrogen atom or a C1-2 alkyl, C1-2 fluoroalkyl or C1-2 perfluoroalkyl group, in the form of enantiomers, diastereoisomers or mixtures thereof, including racemic mixtures, as well as pharmaceutically acceptable acid addition salts thereof, are provided for therapeutical use.

Description

Benzenesulfonamide derivatives and their preparation and application in the medical field

The present invention relates to benzenesulfonamide derivatives and their preparation and application in the medical field.

The compound of the present invention corresponds to the general formula (I) Among them: R ₁ represents a hydrogen atom, a halogen atom such as chlorine or fluorine, or a straight-chain or branched C _1-4 alkyl or C _1-4 alkoxy group, R ₂ , R ₃ and R ₄ are independent of each other and represent hydrogen atom or C _1-4 linear, branched or cyclic alkyl, and R ₅ represents a hydrogen atom or C _1-2 alkyl, C _1-2 fluoroalkyl or C _1-2 perfluoroalkyl.

The term C _1-4 alkyl includes linear, branched or cyclic alkyl groups having up to 4 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl, Preferably it is C _1-2 alkyl such as methyl, ethyl and the like.

The term C _1-2 fluoroalkyl includes straight chain groups as defined above having 1 to 2 carbon atoms in which at least one hydrogen atom is replaced by fluorine atoms, but not all hydrogen atoms are replaced by fluorine atoms. The term C _1-2 perfluoroalkyl includes linear groups as defined above having 1 to 2 carbon atoms in which all hydrogen atoms are replaced by fluorine atoms.

The term C _1-4 alkoxy includes straight or branched chain groups having up to 4 carbon atoms attached through an oxygen atom, including methoxy, ethoxy, propoxy, isopropoxy, butoxy group, isobutoxy and tert-butoxy, preferably C _1-2 alkoxy such as methoxy, ethoxy and the like.

Compounds of general formula (I) contain one or more asymmetric carbon atoms. They may exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereomers and their mixtures, including racemic mixtures, form part of the present invention.

The compounds of general formula (I) may exist in the form of addition salts with pharmaceutically acceptable acids, which also form part of the present invention. Preferred salts according to the invention are methanesulfonate, oxalate and fumarate.

The compound of general formula (I) wherein R ₅ represents C _1-2 alkyl, C _1-2 fluoroalkyl or C _1-2 perfluoroalkyl exists in the form of cis or trans isomers. These isomers and mixtures thereof form part of the present invention.

Preferred compounds are those _wherein R represents a hydrogen atom, methyl or ethyl, preferably a hydrogen atom or a methyl group, in the form of enantiomers or diastereoisomers or mixtures of these different isomers (including racemic spin mixtures) and their addition salts with pharmaceutically acceptable acids.

Other preferred compounds are those wherein _R represents a hydrogen atom, a fluorine atom, a chlorine atom or a C _1-4 alkoxy group, preferably a methoxy group or an ethoxy group, which are enantiomers or diastereomers Or these different isomer mixtures (including racemic mixtures) and their addition salts with pharmaceutically acceptable acids exist.

Other optional compounds are those in which R _{and R} represent a hydrogen atom, methyl, ethyl or isopropyl, preferably a hydrogen atom, in the form of enantiomers or diastereoisomers or these different isomers It exists in the form of mixtures of conformers (including racemic mixtures) and their addition salts with pharmaceutically acceptable acids.

Among the above-mentioned compounds, the following compounds can be enumerated:

R ₁ represents a hydrogen atom, a fluorine atom, a chlorine atom or a C _1-4 alkoxy group, preferably a methoxy group or an ethoxy group,

R ₂ and R ₃ represent a hydrogen atom, methyl, ethyl or isopropyl, preferably a hydrogen atom,

R ₄ represents a hydrogen atom or C _1-4 straight chain, branched chain or cycloalkyl, and

_R represents a hydrogen atom, a methyl group or an ethyl group, preferably a hydrogen atom or a methyl group, in the form of enantiomers or diastereoisomers or mixtures of these different isomers (including racemic mixtures) and their combinations with the drug Exist in the form of acid addition salts,

The exceptions are as follows:

α-(Aminomethyl)-2-methoxy-5-sulfamoylbenzyl alcohol and its salts,

(+)-α-(Aminomethyl)-2-methoxy-5-sulfamoylbenzyl alcohol and its salts,

(-)-α-(Aminomethyl)-2-methoxy-5-sulfamoylbenzyl alcohol and its salts,

α-(Aminomethyl)-2-chloro-5-sulfamoylbenzyl alcohol and its salts, and

α-(Aminomethyl)-2-fluoro-5-sulfamoylbenzyl alcohol and its salts.

wherein R ₁ represents an alkoxy group and R ₂ , R ₃ represent a hydrogen atom, the compound of general formula (I) can be prepared according to the method shown in Appendix 1, which method comprises the use of ethyl orthoformate in the presence of ammonium chloride Process the benzaldehyde derivative shown in general formula (V), wherein R ₁ as defined above, then add chlorosulfonic acid, with R ₄ NH ₂ amine process the derivative of 5-chlorosulfonylbenzaldehyde shown in general formula (IV) thing, wherein R ₄ is as defined in general formula (I), after this in the presence of zinc iodide, make the 5-sulfamoylbenzaldehyde derivative shown in general formula (III) and trimethylsilyl nitrile (TMSCN) Reaction, and finally in the presence of trimethylsilyl chloride (TMSCl), the compound represented by general formula (II) is reduced with lithium borohydride.

Compounds of general formula (I) can also be prepared from sulfamoylacetophenone derivatives of general formula (XII) according to the method shown in Appendix 2.

If R ₁ is shown in the general formula (I) when it is not an alkyl group, the method includes treating the general formula (XII) 5-sulfamoylphenyl ketone derivative with bromine, and then making the general formula (XI) compound and chlorinated Lithium reaction obtains the compound of general formula (X), then obtains the compound of general formula (IX) with borane reduction, then reacts with sodium azide to obtain the compound of general formula (VIII); or make general formula (XI) and sodium azide Reaction, then react with sodium borohydride to obtain the compound of general formula (VIII); or make the compound of general formula (XI) react with sodium borohydride to obtain the compound of general formula (VII) in the presence of potassium carbonate, finally when R is not _a chlorine atom When, in the presence of palladium-activated carbon catalyst, the compound of general formula (VIII) is treated with hydrogen, or when _R is a chlorine atom, the compound of general formula (VIII) is treated with triphenylphosphine and ammonia successively to obtain the compound of general formula (I) , wherein R ₂ and R ₃ are hydrogen atoms, or treat the compound of general formula (VII) with an amine in the form of R ₂ (R ₃ )NH, wherein R ₂ represents a hydrogen atom or a C _1-4 alkyl group, and R ₃ represents C _1-4 alkyl, obtain R ₂ , R ₃ compounds of general formula (I) as described above, or treat compounds of general formula (VII) with amines of formula R ₂ (Bn)NH, wherein R ₂ represents C _1-4 Alkyl, Bn represent benzyl, obtain the compound of general formula (VI), then use hydrogen reduction in the presence of such as palladium-activated carbon catalyst, obtain _R Be the compound of general formula (I) of alkyl.

When _R is an alkyl group, the method comprises treating a compound of general formula (VII) with benzyltrimethylammonium iodide to obtain a compound of general formula (X) in which _R is an alkyl group, which is then treated as described above, The compound of general formula (I) wherein R ₂ , R ₃ is a hydrogen atom, and R ₁ is an alkyl group can be obtained through intermediate compounds corresponding to general formulas (IX) and (VIII).

其中R₁如通式(I)中所定义，与氯磺酸反应制得形如通式(XIII)的氯磺酰苯基酮衍生物

然后再用形如R₄NH₂的胺处理制得，其中R₄如通式(I)中所定义。R₄代表氢原子的通式(XII)化合物也可通过通式(XVII)化合物，

其中A为通式(I)中所定义的R₁或者为羟基，与硝酸反应制得通式(XVI)硝基苯基酮衍生物，

该通式(XVI)化合物在钯-活性炭的存在下用氢还原，或用氯化亚锡还原得到氨基苯基酮衍生物，若A为羟基，应先用碘代烷处理制得2-烷氧基苯基酮衍生物，最后用亚硝酸钠、氯化亚铜和二氧化硫处理通式(XV)化合物通式(I)化合物的对映体可从通式(XIII)化合物的对映体制得通式(XIII)化合物可通过对映体选择合成，它包括用叠氮化钠处理通式(XI)化合物，

再用所得通式(XVIII)化合物

与(+)-或(-)-B-氯代二异松蒎基硼烷(DIP-Cl)反应分别得到通式(XIII)化合物的(+)和(-)对映体，或者用酶拆分通式(IX)化合物制得，它包括用乙酸处理通式(IX)外消旋化合物，用脂肪酶SP 523(脂肪酶从米曲霉通过再重组DNA技术获得)选择性酶水解由此所得的通式(XIX)化合物，

形成通式(IX)化合物的(+)对映体和未水解通式(XIX)化合物的(-)对映体，色谱分离通式(IX)化合物的(+)对映体和未水解通式(XIX)化合物的(-)对映体，水解通式(XIX)化合物的(-)对映体制得通式(IX)化合物的(-)对映体，最后通式(IX)化合物的(+)和(-)对映体与叠氮化钠反应，或者用化学拆分通式(IX)化合物制得，它包括通式(XIII)化合物与N-苄氧羰基-L-丙氨酸(N-CBZ-丙氨酸)，经色谱分离后水解通式(XX)对映体

Compound of general formula (VII) Wherein R ₁ , R ₄ and R ₅ are as defined in the general formula (I), which can be obtained by the phenyl ketone derivatives shown in the general formula (XIV)

Wherein _R As defined in the general formula (I), react with chlorosulfonic acid to obtain the chlorosulfonyl phenyl ketone derivative of the general formula (XIII)

This is then prepared by treatment with an amine of the form R ₄ NH ₂ , wherein R ₄ is as defined in general formula (I). _R The compound of general formula (XII) that represents a hydrogen atom can also pass through the compound of general formula (XVII),

Wherein A is _R as defined in general formula (I) Or is hydroxyl, reacts with nitric acid and makes general formula (XVI) nitrophenyl ketone derivative,

The compound of general formula (XVI) is reduced with hydrogen in the presence of palladium-activated carbon, or with tin protochloride reduction to obtain aminophenyl ketone derivatives, if A is a hydroxyl group, it should be treated with iodoalkane to obtain 2-alkane Oxyphenyl ketone derivatives, finally treating the compound of general formula (XV) with sodium nitrite, cuprous chloride and sulfur dioxide Enantiomers of compounds of general formula (I) can be obtained from enantiomers of compounds of general formula (XIII) Compounds of general formula (XIII) can be synthesized by enantioselection, which includes treating compounds of general formula (XI) with sodium azide,

Then use gained general formula (XVIII) compound

Reaction with (+)- or (-)-B-chlorodiisopine pinocampyl borane (DIP-Cl) to obtain (+) and (-) enantiomers of the compound of general formula (XIII) respectively, or use enzyme Resolution general formula (IX) compound obtains, It comprises processing general formula (IX) racemic compound with acetic acid, with lipase SP 523 (lipase obtains from aspergillus oryzae by recombination DNA technology) selective enzymatic hydrolysis thus gained general formula (XIX) compound,

Form the (+) enantiomer of the compound of general formula (IX) and the (-) enantiomer of the compound of unhydrolyzed general formula (XIX), and chromatographically separate the (+) enantiomer of the compound of general formula (IX) and the unhydrolyzed enantiomer of the compound of general formula (XIX). (-) enantiomer of formula (XIX) compound, (-) enantiomer of hydrolysis general formula (XIX) compound obtains (-) enantiomer of general formula (IX) compound, final general formula (IX) compound (+) and (-) enantiomers are reacted with sodium azide, or prepared by chemical resolution of compounds of general formula (IX), which include compounds of general formula (XIII) and N-benzyloxycarbonyl-L-alanine Acid (N-CBZ-alanine), hydrolyzed enantiomer of general formula (XX) after chromatographic separation

Salts of compounds of general formula (I) are prepared by reacting compounds of general formula (I) in the form of bases with pharmaceutically acceptable acids.

Starting materials are known in the literature or are directly commercially available.

The following examples illustrate preparation methods and techniques suitable for the present invention and are not intended to limit the scope of the claims. Elemental microanalysis and NMR and IR spectroscopy were used to verify the structure of the obtained compounds. Example 1: α-(aminomethyl)-2-methoxy-5-sulfamoylbenzyl methanesulfonate 1.1 2-methoxy-5-sulfamoylbenzaldehyde This compound is based on French patent FR 73 The method in /35277, the chloroform solution that passes ammonia gas into 2-methoxyl-5-chlorosulfonylbenzaldehyde is made. Following the same _procedure , 2-methoxy-5-chlorosulfonylbenzaldehyde was treated with 10 equivalents of an amine of general formula _R4NH2 at room temperature for 3 hours to obtain the following compound: 2-methoxy-5 -Methylsulfamoylbenzaldehyde, melting point: 118°C; 2-methoxy-5-cyclopropylsulfamoylbenzaldehyde, melting point: 162°C; 2-methoxy-5-isopropylsulfamoylbenzaldehyde Benzaldehyde, melting point: 125°C; 2-methoxy-5-tert-butylsulfamoylbenzaldehyde, melting point: 99°C. 1.2 α-Aminomethyl-2-methoxy-5-sulfamoylbenzyl alcohol

Add 10.4 g (48.3 mmol) 2-methoxy-5-sulfamoylbenzaldehyde and 18.4 ml (96.6 mmol) trimethylsilylnitrile to a 100 ml round bottom flask, then add 0.5 g (1.56 mmol) iodide Zinc, the mixture was stirred at room temperature for 10 min. Then 20ml of anhydrous tetrahydrofuran was added, and the solution was transferred to a dropping funnel.

Separately, 100 ml of anhydrous tetrahydrofuran and 2.6 g (119 mmol) of lithium borohydride were added to a 500 ml round bottom flask. After stirring, 30 ml (236 mmol) of trimethylsilyl chloride was added dropwise, and the mixture was stirred at room temperature for 10 minutes.

Then the trimethylsilanol solution prepared above was added dropwise. The mixture was stirred for 16 hours, then 20 mL of ethanol was added dropwise and the solution was concentrated. Then 120ml of 20% potassium hydroxide solution was added dropwise to concentrate the solution. The residue was purified by column chromatography eluting with a 90:9:1 mixture of dichloromethane, methanol and ammonia, then recrystallized from ethanol and dried in a desiccator under vacuum over phosphorus pentoxide. 0.30 g of product is obtained. Melting point: 217-220°C. 1.3 α-Aminomethyl-2-methoxy-5-sulfamoylbenzyl methanesulfonate

To the product obtained in step 1.2 was added 1 equivalent of 2M methanesulfonic acid in methanol. After recrystallization from methanol and ether, vacuum dry in a desiccator filled with phosphorus pentoxide. 0.370 g of product is obtained. Melting point: 210-212°C. Embodiment 2: (-)-α-(aminomethyl)-2-methoxyl-5-sulfamoylbenzyl methanesulfonic acid 2.1 2-methoxyl-5-chlorosulfonylacetophenone

Into a 11 round bottom flask was added 951 grams (8.16 mol) of chlorosulfonic acid. The mixture was cooled to about -5°C, and then 81.5 g (0.544 mol) of 2-methoxyacetophenone was added dropwise at no higher than 0°C. The mixture was stirred at room temperature for 16 hours, then poured slowly with stirring onto crushed ice. The product was filtered off, washed with ice-cold water, and dried under vacuum in a desiccator over phosphorus pentoxide. 87.5 g of product were obtained. Melting point: 85-86°C. 2.2 2-methoxy-5-sulfamoylacetophenone

86 grams (0.344 mol) of 2-methoxy-5-chlorosulfonylacetophenone and 690 ml of chloroform were added to a 11 round bottom flask. Stir to dissolve, then cool to 0°C in an ice bath, and pass ammonia gas for 1 hour. The mixture was warmed to room temperature, and after evaporation of the solvent, 250 ml of 1M hydrochloric acid was added. The resulting suspension was stirred for 3 hours and the product was filtered off, washed with ice-cold water and dried in a desiccator under vacuum over phosphorus pentoxide. 72.8 g of product were obtained. Melting point: 161-162°C. According to the same method, 2-methyl-5-sulfamoylacetophenone was obtained. Melting point: 215°C. 2.3 α-Bromo-2-methoxy-5-sulfamoylacetophenone

Add 60.36 g (0.262 mol) of 2-methoxy-5-chlorosulfonylacetophenone and 530 ml of acetic acid into a 1 l three-necked flask. The mixture was stirred and heated to 50°C. 41.95 g (0.262 mol) of bromine was added dropwise, and the mixture was stirred for 16 hours while the temperature returned to room temperature, and filtered. The precipitate was washed with as little ethanol as possible and dried under vacuum in a desiccator filled with phosphorus pentoxide. 49 g of product were obtained. Melting point: 154-156°C. 2.4 α-Azido-2-methoxy-5-sulfamoylacetophenone

Add 7 grams (0.023mol) of α-bromo-2-methoxy-5-sulfamoylacetophenone, 2.6ml (0.045mol) of acetic acid and 23ml of ethanol into a 100ml three-necked flask. The suspension was heated to 50°C with stirring, and a solution prepared by dissolving 2.94 g (0.045 mol) of sodium azide in 8 ml of water was added dropwise. The suspension was stirred at 50°C for 45 minutes and allowed to cool to room temperature. The precipitate was filtered off, washed with as little cold ethanol as possible, and dried in a desiccator under vacuum over phosphorus pentoxide. 5.46 g of product were obtained. Melting point: 155-160°C (with decomposition). 2.5 (-)-α-Azidomethyl-2-methoxy-5-sulfamoylbenzyl alcohol

Add 16.2 g (0.060 mol) of α-azido-2-methoxy-5-sulfamoylacetophenone and 240 ml of anhydrous tetrahydrofuran into a 500 ml three-necked flask. The solution was cooled to -25°C, and then a solution prepared by dissolving 38.5 g (0.12 mol) of (-)-DIP-Cl in 30 ml of anhydrous tetrahydrofuran was added at a flow rate of 1.5 ml/min. After 90 minutes, the solution was warmed to room temperature, and 10 ml of methanol was added. The reaction mixture was concentrated, and the residue was purified by column chromatography using a 40:60 mixture of petroleum ether and ethyl acetate as eluent. After recrystallization from isopropanol, vacuum dry in a desiccator with phosphorus pentoxide. 11.55 g of product were obtained (ee=99.9%). Melting point: 122-125°C. [α] _D ²⁰ =-147.7°(c=1, dimethyl sulfoxide) 2.6 (-)-α-aminomethyl-2-methoxy-5-sulfamoylbenzyl alcohol

11 g (0.040 mol) of (-)-α-azidomethyl-2-methoxy-5-sulfamoylbenzyl alcohol, 500 ml of ethanol and 2.2 g of 10% palladium-activated carbon were added to a 1 l reactor. The reactor was sealed and purged with nitrogen, hydrogen at 400 kPa was maintained at room temperature and stirred for 3 hours. The reaction mixture was filtered with Whatman paper, the recovered catalyst was suspended in 200 ml of methanol, and the mixture was heated to boil for 30 minutes. It was then filtered through Whatman paper, the combined filtrates were concentrated, and the residue was vacuum dried in a desiccator over phosphorus pentoxide. 9.4 g of (-)-α-aminomethyl-2-methoxy-5-sulfamoylbenzyl alcohol are obtained.

After recrystallization of the product in 388 ml of methanol, 5.46 g of product were obtained. Moreover, after concentrating the mother liquor and recrystallizing with 400ml of ethanol, 1.93 grams of the product were obtained, i.e. a total of 7.39 grams of the product was obtained. Melting point: 217-220°C. [α] _D ²⁰ ＝-85.2°(Methanol) 2.7 Methanesulfonic acid (-)-α-aminomethyl-2-methoxy-5-sulfamoylbenzyl ester

1 equivalent of 2M methanesulfonic acid in methanol was added to the previous product. After recrystallization from methanol and ether, vacuum dry in a desiccator filled with phosphorus pentoxide. (-)-α-Aminomethyl-2-methoxy-5-sulfamoylbenzyl methanesulfonate is obtained. Melting point: 232-233°C. [α] _D ²⁰ = -41.0° (c = 0.796, water) Example 3: (+)- and (-)-methanesulfonic acid α-(aminomethyl)-2-methoxy-5-sulfamic acid Acylbenzoyl 3.1 α-Chloro-2-methoxy-5-sulfamoylacetophenone

Into a 500 ml round bottom flask was added 4.36 grams (14.1 mmol) of α-bromo-2-methoxy-5-sulfamoylacetophenone, 200 ml of anhydrous acetone and 50 grams of lithium chloride. The mixture was heated to reflux for 16 hours, the solution was concentrated, 200 ml of water was added, and extracted 3 times with 80 ml of ethyl acetate. The organic phases were combined, dried over magnesium sulfate and concentrated. 3.56 g of product are obtained. Melting point: 162°C. 3.2 α-Chloromethyl-2-methoxy-5-sulfamoylbenzyl alcohol

To a 100ml round bottom flask was added 10ml of anhydrous tetrahydrofuran and 4ml of 1M borane in tetrahydrofuran. Then, a solution prepared by dissolving 1.0 g (3.8 mmol) of α-chloro-2-methoxy-5-sulfamoylacetophenone in 10 ml of tetrahydrofuran was added dropwise. The mixture was stirred at room temperature for 10 hours, then 10 ml of methanol were added. The solution was concentrated, 40 ml of water was added, and extracted 3 times with 60 ml of ethyl acetate. The organic phases were combined, dried over magnesium sulfate and concentrated. 1.0 g of product was obtained. Melting point: 112°C. 3.3 (±)-α-Chloromethyl-2-methoxy-5-sulfamoylbenzyl acetate

Into a 250 ml round bottom flask was added 2.64 grams (9.9 mmol) of α-chloromethyl-2-methoxy-5-sulfamoylbenzyl alcohol and 100 ml of dichloromethane. Then 10 ml of dimethylformamide, 852 μl of acetic acid, 2.56 g of dicyclohexylcarbodiimide and 121 mg of dimethylaminopyridine were added successively with stirring. The mixture was reacted at room temperature for 1 hour, filtered, and rinsed successively with 50 ml of 5% sodium bicarbonate solution and 50 ml of water. The rinse solution was extracted twice with 20 ml of acetic acid, and the organic phases were combined, dried and concentrated. Using a 25:75 mixture of ethyl acetate and cyclohexane as the eluent, the residue was chromatographed on a silica gel column to obtain 1.9 g of the product. Melting point: 131°C. 3.4 (+)- and (-)-α-chloromethyl-2-methoxy-5-sulfamoylbenzyl alcohol

Add 2.86 g (9.3 mmol) (±) α-chloromethyl-2-methoxy-5-sulfamoylbenzyl acetate and 110 ml tert-butyl methyl ether into a 500 ml three-necked flask. The mixture was stirred for 15 minutes, then 170 ml of phosphate buffered saline was added and stirred vigorously until an emulsion formed. Add 0.57 gram (20%) lipase SP 523 then, add 1M sodium hydroxide stable pH value and monitor reaction with the HPLC of chiral column at room temperature, measure the tumbling degree of ester and the enantiomeric residual amount of ester and alcohol. After reacting for 45 hours, when the remaining enantiomers of ester and alcohol were higher than 95%, the reaction mixture was diluted with 800ml ethyl acetate, the organic phase was separated, and the aqueous phase was extracted 3 times with 500ml ethyl acetate. The organic phases were combined, dried and concentrated, using a 30:70 mixture of ethyl acetate and cyclohexane as the eluent, and the residue was separated on a silica gel column by two-stage flash chromatography to obtain 1.32 g of acetic acid (-)-α -Chloromethyl-2-methoxy-5-sulfamoylbenzyl ester (ee=99%) and 1.05 g (+)-α-chloromethyl-2-methoxy-5-sulfamoylbenzene Methanol.

The (+) enantiomer was dissolved in 10 ml of ethyl acetate and recrystallized by adding cyclohexane (ee=98%). Melting point: 117-118°C. [α] _D ²⁰ = +40° (c = 0.305, methanol)

61 µl of acetyl chloride was added to 100 ml of methanol, and the mixture was stirred for 15 minutes. Then 1.32 g of (-)-acetic acid α-chloromethyl-2-methoxy-5-sulfamoylbenzyl ester was added, and the mixture was heated to reflux for 1 hour (HPLC indicated that the degree of inversion was 97%). The mixture was evaporated, the residue was taken up in 100 ml of ethyl acetate, and the reaction mixture was neutralized with 5 ml of 2% ethyl bicarbonate. The carbonate phase was extracted twice with 5 ml of ethyl acetate, the organic phases were combined, dried, concentrated to 30 ml, and cyclohexane was added. After overnight at room temperature, the crystalline product was filtered off. 1 g of (-)-α-chloromethyl-2-methoxy-5-sulfamoylbenzyl alcohol is obtained. Melting point: 114-115°C. [α] _D ²⁰ ＝-41.4°(c=0.295, methanol) 3.5 (+)-α-azidomethyl-2-methoxy-5-sulfamoylbenzyl alcohol

To a 250 ml round bottom flask was added 1.58 g (5.9 mmol) of (+)-α-chloromethyl-2-methoxy-5-sulfamoylbenzyl alcohol, 20 ml of dimethylformamide and 1.54 g of sodium azide . The reaction mixture was heated to 110°C for 16 hours, added with 200 ml of water, and extracted 3 times with 80 ml of ethyl acetate. The organic phases were combined, dried over magnesium sulfate and concentrated. 1.2 g of product are obtained. Melting point: 122°C. [α] _D ²⁰ =+144° (c=1, dimethyl sulfoxide)

In the same way, from (-)-α-chloromethyl-2-methoxy-5-sulfamoylbenzyl alcohol, (-)-α-azidomethyl-2-methoxy-5- Sulfamoylbenzyl alcohol. Melting point: 122°C. [α] _D ²⁰ ＝-147.7°(c=1, dimethyl sulfoxide) 3.6 (+)-α-aminomethyl-2-methoxy-5-sulfamoylbenzyl alcohol

According to the conditions described in step 6 in Example 2, (+)-α-aminomethyl- 2-Methoxy-5-sulfamoylbenzyl alcohol. Melting point: 217-220°C. [α] _D ²⁰ =+40° (c=1, dimethyl sulfoxide)

In the same way, from (-)-α-azidomethyl-2-methoxy-5-sulfamoylbenzyl alcohol, (-)-α-aminomethyl-2-methoxy-5- Sulfamoylbenzyl alcohol. Melting point: 217-220°C. [α] _D ²⁰ ＝-44°(c=1, dimethyl sulfoxide) 3.7 (+)-methanesulfonic acid α-aminomethyl-2-methoxy-5-sulfamoylbenzyl ester

(+)-α-Aminomethyl-2-methoxy-5-sulfamoylbenzyl alcohol was treated with 1 equivalent of 2M methanesulfonic acid in methanol, recrystallized in methanol and ether, Dry in vacuum in a desiccator. (+)-α-Aminomethyl-2-methoxy-5-sulfamoylbenzyl methanesulfonate is obtained. Melting point: 234°C. [α] _D ²⁰ =+41° (c=0.9945, water)

According to the same method, (-)-methanesulfonic acid α-aminomethyl-2-methoxy- 5-sulfamoylbenzyl ester. Melting point: 235°C. [α] _D ²⁰ = -37.3° (c = 0.969, methanol/water 80:20) Example 4: (+)- and (-)-methanesulfonic acid α-aminomethyl-2-methoxy-5 -sulfamoylbenzyl ester 4.1 (±)-α-azidomethyl-2-methoxy-5-sulfamoylbenzyl alcohol

Into a 500 ml round bottom flask was added 5 grams (18.5 mmol) of α-azido-2-methoxy-5-sulfamoylacetophenone and 150 ml of methanol. The mixture was cooled to 0°C, then 0.963 g (16.6 mmol) of sodium borohydride was added. The solution was stirred for 10 minutes, returned to room temperature, and 15ml of 5% hydrochloric acid was added. The reaction mixture was concentrated, and the residue was purified by column chromatography using a 40:60 mixture of petroleum ether and ethyl acetate as eluent. Dry in vacuum in a desiccator filled with phosphorus pentoxide. 3.85 g of product were obtained. Melting point: 123°C. 4.2 (+)- and (-)-N-benzyloxycarbonyl-L-alanine α-azidomethyl-2-methoxy-5-sulfamoylbenzyl ester

Into a 250 ml round bottom flask was added 4.66 grams (20.9 mmol) of N-benzyloxycarbonyl-L-alanine, 25 ml of dichloromethane and 3.58 grams (17.4 mmol) of 1,3-dicyclohexylcarbodiimide. The mixture was stirred at room temperature for 20 minutes, and 3.8 g (13.9 mmol) of α-azidomethyl-2-methoxy-5-sulfamoylbenzyl alcohol and 0.17 g (0.14 mmol) of dimethylaminopyridine were added. The reaction mixture was stirred for 2 hours, concentrated under reduced pressure, using a 99:1 mixture of dichloromethane and acetone as the eluent, and the residue was separated on a silica gel column by multistage chromatography to obtain 1.58 g of (+)-N- Benzyloxycarbonyl-L-alanine α-azidomethyl-2-methoxy-5-sulfamoylbenzyl ester and 2.92 g of (-)-N-benzyloxycarbonyl-L-alanine α- Azidomethyl-2-methoxy-5-sulfamoylbenzyl ester. Melting point: 170°C (decomposition). 4.3 (+)-Azidomethyl-2-methoxy-5-sulfamoylbenzyl alcohol

Add 0.91 g (1.9 mmol) (+)-N-benzyloxycarbonyl-L-alanine α-azidomethyl-2-methoxyl-5-sulfamoylbenzyl ester, 20ml of ethanol and 3ml of 1M potassium hydroxide solution with a 1:1 mixture of ethanol and water as solvent. The reaction mixture was stirred at room temperature for 25 minutes, concentrated under reduced pressure, and a 95:5 mixture of dichloromethane and methanol was used as the eluent, and the residue was purified by column chromatography. 0.41 g of product are obtained. Melting point: 122°C.

According to the same method, (-)-α- Azidomethyl-2-methoxy-5-sulfamoylbenzyl alcohol. Melting point: 122°C. 4.4 (+)-α-Aminomethyl-2-methoxy-5-sulfamoylbenzyl methanesulfonate

(+)-α-azidomethyl-2-methoxy-5-sulfamoylbenzyl alcohol was hydrogenated according to the conditions described in step 6 of Example 2, and then treated with 1 equivalent of methanesulfonic acid to obtain (+ )-α-aminomethyl-2-methoxy-5-sulfamoylbenzyl methanesulfonate. Melting point: 235°C. [α] _D ²⁰ =+35° (c=1, methanol/water 80:20)

According to the same method, (-)-methanesulfonic acid α-aminomethyl-2-methoxy can be obtained from (-)-α-azidomethyl-2-methoxy-5-sulfamoylbenzyl alcohol -5-sulfamoylbenzyl ester. Melting point: 233°C. [α] _D ²⁰ = -41.8° (c = 1, methanol/water 80:20) Example 5: Methanesulfonic acid α-diethylaminomethyl-2-methoxy-5-sulfamoylbenzidine Ester 5.1 2-Methoxy-5-sulfamoylstyrene oxide

Into a 100 ml round bottom flask were added 2 g (6.5 mmol) of α-bromo-2-methoxy-5-sulfamoylacetophenone, 20 ml of absolute ethanol and 1.0 g (7.0 mmol) of potassium carbonate. Then 0.41 g (10.8 mmol) of sodium borohydride was added, the mixture was stirred at room temperature for 20 minutes, 0.1 M sodium hydroxide was added, and the mixture was stirred for 30 minutes. The solution was concentrated, 30 ml of water was added, and extracted 3 times with 30 ml of ethyl acetate. The organic phases were combined, dried over magnesium sulfate and concentrated. 1.41 g of product are obtained. Melting point: 118°C. 5.2. α-Diethylaminomethyl-2-methoxy-5-sulfamoylbenzyl methanesulfonate

Into a 100 ml round bottom flask was added 1.41 g (6.1 mmol) of 2-methoxy-5-sulfamoylstyrene oxide, 10 ml of absolute ethanol and 17.8 g (244 mmol) of diethylamine. The mixture was heated to reflux for 16 hours. The solution was concentrated and the residue was purified by column chromatography using a 90:9:1 mixture of dichloromethane, methanol and ammonia as eluent, and dried in a desiccator under vacuum over phosphorus pentoxide. 1.42 g of product as an oil were obtained and treated with 1 equivalent of 2M methanesulfonic acid in methanol. After recrystallization in methanol and ether, vacuum drying in a desiccator equipped with phosphorus pentoxide to obtain 0.875 g of α-diethylaminomethyl-2-methoxy-5-sulfamoylbenzene methanesulfonate ester. Melting point: 90-92°C. Example 6: α-Methylaminomethyl-2-methoxy-5-sulfamoylbenzyl methanesulfonate 6.1. α-Benzylmethylaminomethyl-2-methoxy-5-ammonia Sulfonyl benzyl alcohol

The oxidized 2-methoxy-5-sulfamoylstyrene obtained in step 1 of Example 4 was treated with benzylmethylamine under the conditions described in step 2 of Example 4 to give α-benzyl Methylaminomethyl-2-methoxy-5-sulfamoylbenzyl alcohol. 6.2. α-Methylaminomethyl-2-methoxy-5-sulfamoylbenzyl methanesulfonate

To 1.90 g (5.4 mmol) of α-benzylmethylaminomethyl-2-methoxy-5-sulfamoylbenzyl alcohol, hydrogenation according to the conditions described in step 6 in Example 2 gave α-methylammonia Methyl-2-methoxy-5-sulfamoylbenzyl alcohol. After recrystallization from methanol and ether, the resulting product was treated with 1 equivalent of 2M methanesulfonic acid in methanol and the resulting salt was recrystallized from methanol, dichloromethane and ether to obtain 0.396 g of α-methylaminomethyl-2 methanesulfonate -Methoxy-5-ammonia. Sulfonyl benzoate. Melting point: 194-196°C. Example 7: α-aminomethyl-2-fluoro-5-sulfamoylbenzyl methanesulfonate 7.1 2-fluoro-5-nitroacetophenone

Add 25ml (180mmol) of 2-fluoro-acetophenone into a 100ml three-neck flask filled with 60ml of concentrated sulfuric acid cooled to -5°C. Then a mixture of 14ml of nitric acid (d=1.42) and 20ml of concentrated sulfuric acid was added dropwise, and the temperature was controlled below 0°C. Stir at -5°C for 30 minutes, then pour onto crushed ice. The resulting mixture was extracted three times with 60 ml of ethyl acetate, and the organic phases were combined, dried over magnesium sulfate and concentrated. Using a 70:30 mixture of cyclohexane and ethyl acetate as the eluent, the residue was purified on a chromatographic column and dried under vacuum in a desiccator filled with phosphorus pentoxide. 26 grams of product were obtained. Melting point: 72°C.

In the same way, 2-chloro-5-nitroacetophenone was obtained. Melting point: 65°C. -2-Hydroxy-5-nitroacetophenone melting point: 98°C, it can be converted into 2-isopropoxy-5-nitroacetophenone through phase transfer catalytic reaction with iodoisopropane. Melting point: 78°C. 7.2.5-Amino-2-fluoroacetophenone

Add 25.4 g (152 mmol) of 2-fluoro-5-nitroacetophenone, 343 g (1.52 mmol) of anhydrous stannous chloride and 250 ml of ethyl acetate into a 1 l three-necked flask. The reaction mixture was heated to 70°C for 30 minutes. Then it was poured onto 1 liter of crushed ice, 30% sodium hydroxide solution was added, and the resulting mixture was extracted 3 times with 350 ml of ethyl acetate. The organic phases were combined, dried over magnesium sulfate and concentrated. 11.26 g of oily product are obtained.

According to the same method, the following compounds were obtained:

-5-Amino-2-chloroacetophenone, oil,

-5-Amino-2-isopropoxyacetophenone, oily.

7.3.2-Fluoro-5-sulfamoylacetophenone

Add 50 ml of concentrated hydrochloric acid to a 250 ml three-neck flask containing 15.3 g (100 mmol) of 5-amino-2-fluoroacetophenone and 50 ml of acetic acid. The reaction mixture was cooled to 0°C, and a solution prepared by dissolving 10.3 g (150 mmol) of sodium nitrate in 25 ml of water was added dropwise, and maintained at 0°C for 30 minutes. Then add 5 grams (29 mmol) of cuprous chloride dihydrate and a suspension formed by dissolving 30 grams (470 mmol) of sulfur dioxide in 75 ml of acetic acid and cooling to -15°C. The mixture was kept at 0° C. for 48 hours, then 20 ml of water was added, the resulting mixture was extracted 3 times with 120 ml of dichloromethane, and the combined organic phases were dried over magnesium sulfate and concentrated.

The residue was dissolved in 100ml of tetrahydrofuran, and a 28% aqueous ammonia solution was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 16 hours and concentrated. The residue was purified by column chromatography eluting with a 60:40 mixture of hexane and ethyl acetate. Vacuum drying in a desiccator filled with phosphorus pentoxide yielded 11.23 g of product. Melting point: 112°C.

According to the same method, the following compounds were obtained: -2-chloro-5-sulfamoylacetophenone, melting point: 106°C; -2-isopropoxy-5-sulfamoylacetophenone, melting point: 85°C;- 3-Sulfamoylacetophenone, melting point: 144°C. 7.4. α-Bromo-2-fluoro-5-sulfamoylacetophenone

2-Fluoro-5-sulfamoylacetophenone was treated under the conditions described in step 3 of Example 2 to obtain α-bromo-2-fluoro-5-sulfamoylacetophenone. Melting point: 122°C.

According to the same method, the following compounds were obtained: -α-bromo-2-chloro-5-sulfamoylacetophenone, melting point: 126°C; -α-bromo-2-isopropoxy-5-sulfamoylacetophenone Ketone, melting point: 105°C; -α-bromo-3-sulfamoylacetophenone, melting point: 130°C. 7.5. α-Chloro-2-fluoro-5-sulfamoylacetophenone

α-Bromo-2-fluoro-5-sulfamoylacetophenone was treated under the conditions described in step 1 of Example 3 to obtain α-chloro-2-fluoro-5-sulfamoylacetophenone. Melting point: 114°C.

According to the same method, the following compounds were obtained: -α-chloro-2-chloro-5-sulfamoylacetophenone, melting point: 124°C; -α-chloro-2-isopropoxy-5-sulfamoylacetophenone Ketone, melting point: 98°C; -α-chloro-3-sulfamoylacetophenone, melting point: 128°C. 7.6.α-Chloromethyl-2-fluoro-5-sulfamoylbenzyl alcohol

α-Chloro-2-fluoro-5-sulfamoylacetophenone was treated according to the conditions described in step 2 of Example 3 to obtain α-chloromethyl-2-fluoro-5-sulfamoylbenzyl alcohol. Melting point: 112°C.

According to the same method, the following compounds were obtained: -α-chloromethyl-2-chloro-5-sulfamoylbenzyl alcohol, melting point: 115 ° C; -α-chloromethyl-2-isopropoxy-5-sulfamoyl Acylbenzyl alcohol, melting point: 93°C; -α-chloromethyl-3-sulfamoylbenzyl alcohol; melting point: 122°C. 7.7. α-Azidomethyl-2-fluoro-5-sulfamoylbenzyl alcohol

α-Chloromethyl-2-fluoro-5-sulfamoylbenzyl alcohol was treated according to the conditions described in Step 4 of Example 3 to obtain α-azidomethyl-2-fluoro-5-sulfamoylbenzyl alcohol. Melting point: 86°C. According to the same method, the following compounds were obtained: -α-azidomethyl-2-chloro-5-sulfamoylbenzyl alcohol, melting point: 122°C; -α-azidomethyl-2-isopropoxy-5- Sulfamoylbenzyl alcohol, melting point: 95°C; -α-azidomethyl-3-sulfamoylbenzyl alcohol, melting point: 118°C. 7.8. α-Aminomethyl-2-fluoro-5-sulfamoylbenzyl methanesulfonate

α-Azidomethyl-2-fluoro-5-sulfamoylbenzyl alcohol was treated according to the conditions described in step 6 of Example 2 to obtain α-aminomethyl-2-fluoro-5-sulfamoylbenzyl methanesulfonate ester. Melting point: 164°C. Example 8: α-Aminomethyl-2-methyl-5-sulfamoylbenzyl methanesulfonate 8.1.α-Chloro-2-methyl-5-sulfamoylacetophenone

In the 500ml round bottom flask, add 26.4 grams (76.0mmol) benzyltrimethylammonium iodide (prepared with reference to the method described in "Synthesis" volume 7 (1988) page 545), 9.25 grams (43.4mmol ) 2-methyl-5-sulfamoylacetophenone, 90 ml methanol and 220 ml 1,2-dichloroethane. The reaction mixture was heated to reflux for 16 hours, concentrated, and 200 ml of saturated sodium bicarbonate solution was added. The resulting mixture was extracted three times with 120 ml of ethyl acetate, and the combined organic phases were dried over magnesium sulfate and concentrated. The residue was purified by column chromatography using a 60:40 mixture of hexane and ethyl acetate as the eluent, and dried in a desiccator filled with phosphorus pentoxide in vacuo. 1.7 g of product are obtained. Melting point: 114°C. 8.2. α-Chloromethyl-2-methyl-5-sulfamoylbenzyl alcohol

α-Chloro-2-methyl-5-sulfamoylacetophenone was treated according to the conditions described in step 2 of Example 3 to obtain α-chloromethyl-2-methyl-5-sulfamoylbenzyl alcohol. Melting point: 126°C. 8.3. α-Azidomethyl-2-methyl-5-sulfamoylbenzyl alcohol

α-Chloromethyl-2-methyl-5-sulfamoylbenzyl alcohol was treated according to the conditions described in step 4 of Example 3 to obtain α-azidomethyl-2-methyl-5-sulfamoylbenzyl alcohol. Melting point: 98°C. 8.4. α-Aminomethyl-2-methyl-5-sulfamoylbenzyl methanesulfonate

α-Azidomethyl-2-methyl-5-sulfamoylbenzyl alcohol was treated according to the conditions described in step 6 of Example 2 to obtain methanesulfonic acid α-aminomethyl-2-methyl-5-sulfamoyl Benzyl esters. Melting point: 185°C. Example 9: α-aminomethyl-2-chloro-5-sulfamoylbenzyl methanesulfonate

Add 1.35 g (4.9 mmol) of α-azidomethyl-2-chloro-5-sulfamoylbenzyl alcohol, 90 ml of anhydrous pyridine and 9.67 g (29.0 mmol) of triphenylene deposited on a support to a 250 ml round bottom flask phosphine. The mixture was stirred at room temperature for 9 hours, then 100ml of 28% ammonia water was added, the suspension was stirred for 16 hours, and filtered. The filtrate was concentrated, and the residue was recrystallized from methanol. 0.523 g of α-aminomethyl-2-chloro-5-sulfamoylbenzyl alcohol was obtained. 1 equivalent of 2M methanesulfonic acid in methanol was added to the previous product. After recrystallization from methanol and ether, vacuum-dry in a desiccator filled with phosphorus pentoxide to obtain 0.439 g of α-aminomethyl-2-chloro-5-sulfamoylbenzyl methanesulfonate. Melting point: 206-208°C. Example 10: Cis- and trans-(2'-methoxy-5'-sulfamoylphenyl)-2-amino-1-propanol 10.1 2-methoxy-5-chlorosulfonylpropiophenone

2-Methoxypropiophenone was treated according to the conditions described in step 1 of Example 2 to obtain 2-methoxy-5-chlorosulfonylpropiophenone. Melting point: 86-89°C. 10.2 2-Methoxy-5-sulfonylpropiophenone

2-Methoxy-5-chlorosulfonylpropiophenone was treated according to the conditions described in step 2 of Example 2 to obtain 2-methoxy-5-sulfonylpropiophenone. Melting point: 162-165°C. 10.3. 2-Bromo-2′-methoxy-5′-sulfamoylpropiophenone

2-Methoxy-5-sulfonylpropiophenone was treated according to the conditions described in step 3 of Example 2 to obtain 2-bromo-2'-methoxy-5'-sulfamoylpropiophenone. Melting point: 108-110°C. 10.4 2-Azido-2′-methoxy-5′-sulfamoylpropiophenone

α-Bromo-2-methoxy-5-sulfamoylpropiophenone was treated according to the conditions described in step 4 of Example 2 to obtain 2-azido-2'-methoxy-5'-sulfamoylpropiophenone. Melting point: 113-114°C. 10.5. (2′-Methoxy-5′-sulfamoylphenyl)-2-azido-1-propanol

2-Azido-2'-methoxy-5'-sulfamoylpropiophenone was treated according to the conditions described in step 1 of Example 4 to obtain (2'-methoxy-5'-sulfamoylphenyl)- 2-Azido-1-propanol. Melting point: 109-110°C. 10.6. Cis- and trans-(2′-methoxy-5′-sulfamoylphenyl)-2-amino-1-propanol

(2'-methoxy-5'-sulfamoylphenyl)-2-azido-1-propanol was treated according to the conditions described in step 6 of Example 2 to obtain cis- and trans-(2'-methyl Oxygen-5'-sulfamoylphenyl)-2-amino-1-propanol mixtures, which use 95:5:0.5 dichloromethane, methanol and ammonia as eluents, pass through the silica gel column continuously Chromatographic separation affords the cis- and trans-diastereomers.

After recrystallization in isopropanol, vacuum drying in a desiccator with phosphorus pentoxide affords cis-(2′-methoxy-5′-sulfamoylphenyl)-2-amino-1-propane Alcohol, melting point: 176-177°C, and trans-(2'-methoxy-5'-sulfamoylphenyl)-2-amino-1-propanol, melting point: 233-237°C. Example 11: (-)-cis-(2'-methoxy-5'-sulfamoylphenyl)-2-amino-1-propanol 11.1. (-)-cis-(2'-methoxy -5′-sulfamoylphenyl)-2-azido-1-propanol

2-Azido-2'-methoxy-5'-sulfamoylpropiophenone was treated according to the conditions described in step 5 of Example 2, and (-)-cis-(2'- Methoxy-5'-sulfamoylphenyl)-2-azido-1-propanol. Melting point: 143-145°C. [α] _D ²⁰ ＝-125°(methanol) 11.2. (-)-cis-(2′-methoxy-5′-sulfamoylphenyl)-2-amino-1-propanol

(-)-cis-(2'-methoxy-5'-sulfamoylphenyl)-2-azido-1-propanol was treated according to the conditions described in step 6 of Example 2, after two isopropyl Recrystallization of the alcohol gave (-)-cis-(2'-methoxy-5'-sulfamoylphenyl)-2-amino-1-propanol. Melting point: 190-191°C. [α] _D ²⁰ = -34.1° (methanol)

The compounds of the invention and their physical properties are summarized in the table below.

Table 1

MeSO ₃ H stands for mesylate

OMe stands for methoxy

O-iPr stands for isopropoxy

代表环丙基i-Pr stands for isopropyl

Represents cyclopropyl

The compounds of the invention have been subjected to biological tests intended to demonstrate their _α1- adrenoceptor agonist activity.

In particular, they were also tested for binding to the α _1a , α _1b and α _1d subreceptors sequentially on mouse salivary gland tissue, mouse liver tissue and transfected CHO cells, respectively.

The affinity for each sub-receptor expressed by IC ₅₀ (50% inhibition of the concentration of binding to [3H]prazosin) was determined, and the α _1b and α _1d receptor affinity was calculated for α Relative values of _1a receptor affinity expressed as the ratio of IC ₅₀ values: [α _1b /α _1a ] and [α _1d /α _1a ].

For the compounds of the invention, these ratios were 9.3-21.6 and 7.8-20.9, respectively, indicating their remarkable selectivity for the _α1a receptor.

The compounds of the present invention have been tested for in vitro activity on urethral and arterial smooth muscle.

These experiments were performed on female New Zealand rabbits weighing 3-3.5 kg. The animals were sacrificed by spinal dislocation, and tissue rings were removed from the mesenteric artery and urethra. These tissue rings were immersed in modified Krebs solution and oxidized with a mixture of 95% _O2 and 5% _CO2 . Each sample was subjected to a tension of 1 g, and then the corresponding cumulative dose of phenylephrine was added, and a dose/effect curve was established. After rinsing the samples, the corresponding cumulative doses of the test compound were added and a dose/effect curve was established. The α ₁ -adrenergic effect of each compound was calculated by calculating Pd ₂ (the negative logarithm of the antagonist concentration required to halve the agonist dose value), and the maximum effect value representing the percentage of maximum contraction induced by phenylephrine to evaluate (%E _max ).

For the compounds of the present invention, urethral and arterial _Pd values were 4.18-4.93 ( _Pd phenylephrine = 5.2-5.5) and 3.73-4.55 ( _Pd phenylephrine = 5.2-5.5), respectively, urethral and arterial %E _max 58.4-76 and 76-94.6, respectively.

The compound of the present invention has carried out in vivo activity test on blood pressure and urethral pressure of rabbits.

These experiments were performed on female New Zealand rabbits weighing 3-4 kg. After pentobarbital anesthesia, a catheter was introduced through the femoral artery into the accessory aorta, into the jugular vein and urethra (1 cm below the bladder neck).

Test compounds were administered intravenously or orally 5-15 days after surgery.

Intravenously, the compound was administered as a single dose over 5 minutes or cumulatively at 15 minute intervals at a dose of 3-100 μg/kg.

For each dose, blood pressure (BP) and urethral pressure (UP) were measured serially.

For the compounds of the invention, the increase in BP was 5 mmHg at a dose of 10 μg/kg and 15 mmHg at a dose of 100 μg/kg, the increase in UP was 14 _cmH2O at a dose of 10 μg/kg and 54 _cmH2 at a dose of 100 μg/kg O.

In different dosage tests, the compound of the present invention significantly increases urethral pressure without significantly changing blood pressure, and shows strong urethral selectivity.

Orally, compounds were administered by gavage in a single dose of 300 μg/kg-1000 μg/kg in a volume of 1 ml/kg. BP and UP were measured at 5, 10, 30, 45 and 60 minutes after gavage.

For the compounds of the present invention, the changes in BP are about -0.2mmHg and -0.9mmHg after 30 minutes, and about -5.3mmHg and 1.1mmHg after 60 minutes, respectively, at 300 μg/kg and 1000 μg/kg doses, UP At 300 μg/kg and 1000 μg/kg doses, the changes were approximately 1.6 cmH ₂ O and 7.8 cmH ₂ O after 30 minutes, and approximately 3.7 cmH ₂ O and 8.3 cmH ₂ O after 60 minutes.

When administered orally, the compounds of the present invention significantly increased urethral pressure without significantly altering blood pressure, while exhibiting complete urethral selectivity.

The results obtained generally indicate that the compounds of the invention have strong urethral activity and weak arterial activity. They are _α1- adrenoceptor agonists selective for _α1a receptors. They can therefore be used in the treatment of urinary incontinence.

For this purpose, they can be put into a form suitable for enteral or parenteral administration together with pharmaceutical excipients, such as tablets, dragees, capsules including hard gelatine capsules, oral or injectable solutions, suppositories, and A daily release dose of 0.001-1000 mg of active substance is achieved.

attachment1

Annex 2

Claims (15)

1. general formula (I) benzenesulfonamide compounds

Wherein: R ₁Represent hydrogen atom, such as the halogen atom of chlorine or fluorine or the C of straight or branched _1-4Alkyl or C _1-4Alkoxyl group, R ₂, R ₃And R ₄Independently of one another, represent hydrogen atom or C _1-4Straight chain, side chain or cycloalkyl, and R ₅Represent hydrogen atom or C _1-2Alkyl, C _1-2Fluoro-alkyl or C _1-2Perfluoroalkyl, they comprise racemic mixture with the mixture of enantiomorph or diastereomer or these different isomerization bodies, and the form of the adduct of they and medicinal acid exists.

2. according to the compound of claim 1, it is characterized in that R ₅Represent hydrogen atom, methyl or ethyl.

3. according to the compound of claim 1, it is characterized in that R ₁Represent hydrogen atom, fluorine atom, chlorine atom or C _1-4Alkoxyl group.

4. according to the compound of claim 1, it is characterized in that R ₂And R ₃Independently of one another, represent hydrogen atom, methyl, ethyl or sec.-propyl.

5. according to the compound of claim 1, it is characterized in that R ₁Represent hydrogen atom, fluorine atom, chlorine atom or C _1-4Alkoxyl group, R ₂And R ₃Independently of one another, represent hydrogen atom, methyl, ethyl or sec.-propyl, R ₄Represent hydrogen atom or C _1-4Straight chain, side chain or cycloalkyl, and R ₅Represent hydrogen atom, methyl or ethyl.

6. according to the compound of claim 1, it is characterized in that R ₁Represent hydrogen atom, fluorine atom, chlorine atom, methoxy or ethoxy, R ₂And R ₃Represent hydrogen atom, R ₄Represent hydrogen atom or C _1-4Straight chain, side chain or cycloalkyl, and R ₅Represent hydrogen atom or methyl.

7. α-(aminomethyl)-2-methoxyl group-5-sulphonamide phenylcarbinol, its pharmaceutical salts and their enantiomorph.

8. (+)-α-(aminomethyl)-2-methoxyl group-5-sulphonamide phenylcarbinol and pharmaceutical salts thereof.

9. (-)-α-(aminomethyl)-2-methoxyl group-5-sulphonamide phenylcarbinol and pharmaceutical salts thereof.

10. α-(aminomethyl)-2-chloro-5-sulphonamide phenylcarbinol, its pharmaceutical salts and their enantiomorph.

11. α-(aminomethyl)-2-fluoro-5-sulphonamide phenylcarbinol, its pharmaceutical salts and their enantiomorph.

12. curable product is characterized in that it comprises general formula (I) compound according to claim 1.

13. medicinal compositions is characterized in that it comprises general formula (I) compound with the vehicle bonded claim 1 of any appropriate.

14. prepare the method for general formula (I) compound, Wherein: R ₁Represent the C of straight or branched _1-4Alkoxyl group, R ₂And R ₃Represent hydrogen atom, R ₄Represent hydrogen atom or C _1-4Straight chain, side chain or cycloalkyl, and R ₅Represent hydrogen atom, described compound is with the mixture of enantiomorph or diastereomer or these different isomerization bodies, comprise racemic mixture, and the form of the adduct of they and medicinal acid exists, it comprises: (a) make general formula (III) compound in the presence of zinc iodide

R wherein ₁, R ₄As defined above,, obtain general formula (II) derivative with trimethyl silicon based nitrile reaction, R wherein ₁, R ₄As defined above, (b) in the presence of trimethylsilyl chloride, derivative with shown in the general formula (II) of lithium borohydride reduction gained makes general formula (I) compound, (c) randomly gained compound (I) is converted into its enantiomorph or diastereomer or its pharmaceutical salts.

15. prepare the method for general formula (I) compound,

Wherein: R ₁Represent hydrogen atom, such as the halogen atom of chlorine or fluorine or the C of straight or branched _1-4Alkyl or C _1-4Alkoxyl group, R ₂, R ₃And R ₄Independently of one another, represent hydrogen atom or C _1-4Straight chain, side chain or cycloalkyl, and R ₅Represent hydrogen atom or C _1-2Alkyl, C _1-2Fluoro-alkyl or C _1-2Perfluoroalkyl, they comprise racemic mixture with the mixture of enantiomorph or diastereomer or these different isomerization bodies, and the form of the adduct of they and medicinal acid exists, it comprises: (a) randomly carry out following reaction and make general formula (VIII) derivative It comprises that the form of racemic mixture exists, wherein R with the mixture of enantiomorph or diastereomer or these different isomerization bodies ₄And R ₅As defined above, work as R ₁As defined above and the non-chlorine atomic time, such as in the presence of palladium-activated-carbon catalyst with H-H reaction; Perhaps work as R ₁Be the chlorine atomic time, successively with triphenyl phosphine, ammoniacal liquor reaction,

Make general formula (I) compound, wherein R ₁, R ₄And R ₅As defined above, R ₂, R ₃Be hydrogen atom, (b) or randomly carry out following reaction, make general formula (VII) derivative,

R wherein ₁, R ₄And R ₅As defined above, with formula R ₂(R ₃) the amine reaction of NH, wherein R ₂Represent hydrogen atom or C _1-4Alkyl, R ₃Represent C _1-4Alkyl obtains R ₂, R ₃General formula (I) compound as defined above is perhaps with formula R ₂(Bn) amine of NH reaction, wherein R ₂Represent C _1-4Alkyl, Bn represents benzyl; Obtain general formula (VI) derivative, in the presence of catalyzer, use hydrogen reduction then, obtain R such as the palladium gac ₂Be C _1-4The general formula of alkyl (I) compound (c) randomly is converted into gained compound (I) its enantiomorph or diastereomer or its pharmaceutical salts.